MedImmune LLC, One MedImmune Way, Biologics Safety Assessment, Gaithersburg, MD 20878, USA.
Expert Opin Drug Discov. 2010 Jan;5(1):79-94. doi: 10.1517/17460440903443410.
The prediction of human toxicity by employing animal models for nonclinical safety evaluation of pharmaceuticals poses numerous challenges. Each type, biologics, vaccines and small molecules, has unique features, which may impact the ability to effectively assess safety.
The importance of taking a case-by-case approach is highlighted in this review of the challenges encountered in general safety evaluations for biologics and vaccines compared to small molecules.
The reader will gain insights in specific issues related to building a successful predictive nonclinical safety program for biologics.
While there is fair concordance for small molecules, animal models used for the safety evaluation of biologics may have limitations with regard to human relevance. For small molecules, this is commonly because of differences in metabolism profiles or off-target effects. For biologics, which are highly targeted molecules, it may be because of differences in physiological processes or biologic pathways that limit pharmacologic relevance. For vaccines or immunomodulatory biologics, it may be related to the complexities of modeling the human immune system in a nonhuman species. While international guidances are available to govern the nonclinical safety assessment process for human pharmaceuticals (such as ICH M3), in many instances a case-by-case approach is employed for novel agents.
在药物非临床安全性评价中，采用动物模型预测人类毒性存在诸多挑战。每种类型，生物制剂、疫苗和小分子，都具有独特的特征，这可能会影响到有效评估安全性的能力。
在与小分子相比，对生物制剂和疫苗的一般安全性评估中遇到的挑战进行案例分析时，强调了采用具体问题具体分析方法的重要性。
读者将深入了解与成功建立生物制剂预测性非临床安全性计划相关的具体问题。
虽然小分子之间存在一定的一致性，但用于生物制剂安全性评估的动物模型可能与人类相关性存在局限性。对于小分子，这通常是由于代谢谱或脱靶效应的差异所致。对于生物制剂，由于生理过程或生物途径的差异限制了药理相关性，因此可能存在局限性。对于疫苗或免疫调节生物制剂，这可能与在非人类物种中模拟人类免疫系统的复杂性有关。虽然有国际指南来指导人类药物的非临床安全性评估过程（如 ICH M3），但在许多情况下，新型药物仍采用具体问题具体分析的方法。
